PROJECT SUMMARY Melanoma is a skin cancer that accounts for only 4% of cases but 80% of deaths; in 2014 alone it resulted in approximately 10,000 deaths in the United States. Spontaneous development of anti-tumor immunity is associated with improved clinical outcome, indicating the potential for immunotherapy to increase melanoma patient survival. Anti-tumor immune responses are initiated and regulated within sentinel (tumor-draining) lymph nodes (TDLN), but are often inefficient as the result of local immune suppressive signaling. TDLN-directed tumor immune suppression therefore represents a critical hurdle in effective melanoma immunotherapy. Therefore, there is a significant and unmet need for technologies that increase the delivery of immunomodulatory agents to TDLN-resident immune cells improve the treatment of melanoma. The objective of this R01 project is to develop and validate a sentinel lymph node drug delivery technology to improve immunotherapeutic drug bioactivity within melanoma TDLN. This will be tested in a rigorous preclinical inducible model of BRAF mutated melanoma, which occurs in 50% of human melanomas. Three aims are proposed: Aim 1: Measure specificity of drug accumulation in TDLN versus systemic tissues resulting from LN- versus non-targeted immunotherapy. Aim 2: Delineate the immune modulatory effect of LN- versus non-targeted immunotherapy in the BRAFv600E melanoma model. Aim 3: Evaluate the therapeutic efficacy of LN- versus non-targeted immunotherapy alone versus in combination with BRAFv600E inhibition on disease progression and animal survival in the BRAFv600E melanoma model. This project is expected to yield several outcomes. First, these studies will define parameters for enhancing the efficacy of melanoma immunotherapy via LN drug targeting. Second, the potential for TDLN-targeted immunotherapy to improve the efficacy of BRAFv600E inhibition in the treatment of advanced melanomas will be established. Therapeutic agents already in human clinical testing or approved for human use will be investigated in this work to ensure the highest potential for rapid clinical translation.